Visceral glomerular epithelial cells (podocytes) are a component of the glomerular filtration barrier. Due to a lack of ability for post-natal proliferation, the podocyte is a most vulnerable component of the glomerulus, and podocyte injury triggers irreversible change sin many glomerular diseases. The ultimate goal of this project is to elucidate the molecular mechanisms of podocyte damage through the study of the pathogenesis of HIV-1 associated nephropathy (IVAN). In HIVAN, glomeruli show a characteristic change, i.e., collapsing focal segmental glomerulosclerosis (FSGS), in which podocytes lose differentiation markers, proliferative and undergo apoptosis. Similar podocyte dysregulation is observed in idiopathic collapsing glomerulopathy and the FSGS variant with cellular lesion. In addition, down-regulation of differentiation markers occurs also in more common glomerular diseases, including minimal change disease and mesangial proliferative glomerulonephritis. Previous transgenic mouse studies showed than when HIV-1 DNA containing vif, vpr, rev and tat is expressed by the authentic LTR promoter, the kidney develops a renal disease faithfully mimicking human HIVAN. Renal cross transplantation between the transgenic and wild-type mice revealed that the transgene expressed in the kidney causes the renal disease. Based on this information, the following specific aims will be investigated during the first two years. Aim #1. Generation of transgenic mice in which podocyte-specific expression of HIV-1 gene that is essential for the pathogenesis of HIVAN by transgenic mice. These studies will be followed by identification of the specific molecule(s) in podocytes that are associated with the product of the pathogenic HIV-1 gene to ascertain the common mechanism(s) of podocyte dysregulation. Genetic studies of inherited polycystic kidney disease (PKD) in human and animal models have clearly shown that mutations at multiple loci result in various forms of PKD. While the cystogenesis itself is thought to be a primary cause of renal injury, several studies have stressed the important relationship between the onset of tubulointerstitial fibrosis, and the progression to end-stage renal disease. The PI has characterized a mouse model for PKD caused by three independent mutations, kat, kat21, kjat3J, that map to the same locus on Chromosome 8. By positional cloning, she has identified the gene mutated as the NIMA (Never In Mitosis A) related kinase, Nek1. The PI hypothesizes that in the kidney, NEK1 protein belongs to a signaling pathway that promotes the full maturation in renal tubular epithelial cells. The PI has also shown that the loss of Nek1 function leads to an increase in TGFbeta1 mRNA levels in renal interstitial as well as tubular cells. Therefore, these altered/immature renal epithelial cells may not only facilitate renal cystogenesis but also contribute directly to tubulointerstitial fibrosis. The PI is currently examining in her funded RO1 how the loss of Nek1 function leads to renal cystogenesis. In this pilot proposal she will pursue a new area of research: investigating the role of Nek1-null tubular epithelial cells in interstitial fibrosis. The hypotheses to be tested are: 1. The loss of Nek1 expression in renal tubular cells increases the activation of TGFbeta1 in those cells 2. The loss of Nek1 expression in renal tubular cells increases epithelial- mesenchymal transdifferentiation.